Background: Avelumab* is a fully human anti-PD-L1 IgG1 antibody under clinical investigation in multiple cancers. We report safety and clinical activity of avelumab as 1^st-line therapy in patients (pts) with non-small-cell lung cancer (NSCLC) from a phase 1b trial (NCT01772004). Methods: Pts with advanced NSCLC not previously treated systemically for metastatic or recurrent disease, without an activating EGFR mutation or ALK rearrangement, and not selected for PD-L1 expression were treated with avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Responses were evaluated every 6 wks (RECIST 1.1). Adverse events (AEs) were graded by NCI-CTCAE v4.0. PD-L1 expression was assessed by IHC. Results: As of Oct 23, 2015, 145 pts received avelumab (median 10 wks [range 2-30]) and were followed for a median duration of 13 wks (range 0-31). Median age was 70 y (range 41-90), ECOG PS was 0 (31.0%) or 1 (69.0%), and histology was adenocarcinoma (63.4%), squamous (26.9%), other (3.4%), or unknown (6.2%). Treatment-related (TR) AEs occurred in 82 pts (56.6%; all grades); those occurring ≥ 10% were infusion-related reaction (IRR; 24 [16.6%]) and fatigue (21 [14.5%]). Grade ≥ 3 TRAEs were reported in 13 pts (9.0%); only IRR and fatigue occurred in > 1 pt (each 3 [2.1%]). There were no treatment-related deaths. Among 75 pts with ≥ 3 mos f/u, unconfirmed ORR was 18.7% (95% CI: 10.6, 29.3) based on 1 CR and 13 PRs; 12 were ongoing. Stable disease was reported in 34 pts (45.3%); disease control rate was 64.0%. PD-L1 expression was evaluable in 45/75 pts (60.0%). Based on a ≥ 1% cutoff for tumor cell staining, 35/45 (77.8%) were PD-L1+ and ORR was 20.0% in PD-L1+ (7/35; 95% CI: 8.4, 36.9) vs 0/10 (0.0, 30.8) in PD-L1– pts. Median PFS was 11.6 wks (95% CI: 6.7, 17.9) for all treated pts. Conclusions: Single-agent avelumab showed an acceptable safety profile and clinical activity in pts with NSCLC who were EGFR-wildtype and ALK-negative, not previously treated for advanced disease, and unselected for PD-L1 expression. A trend of higher ORR in PD-L1+ tumors is suggested. Phase 3 trials of avelumab in NSCLC are ongoing. *Proposed INN. Clinical trial information: NCT01772004